Gene and methods for diagnosing neuropsychiatric disorders and treating such disorders

ABSTRACT

A mammalian 22444 gene and gene products which are predictive of a susceptibility or predisposition to various neuropsychiatric disorders are provided. Methods of predicting an individual&#39;s susceptibility to developing or having a neuropsychiatric disorder via detection of these diagnostic markers are also provided. In addition, compositions and methods for identifying compositions for use in the treatment of neuropsychiatric disorders via these genes and gene products are described.

This application is a continuation of U.S. patent application Ser. No.10/127,124 filed Apr. 19, 2002, which is a continuation of U.S. patentapplication Ser. No. 09/689,423, filed Oct. 12, 2000, which claims thebenefit of U.S. Provisional Application No. 60/159,354, filed Oct. 14,1999 and U.S. Provisional Application No. 60/195,620 filed Apr. 7, 2000,each of which are herein incorporated by reference in their entireties.This invention was supported in part by funds from the U.S. government(NIMH grant MH59533) and the U.S. government may therefore have certainrights in the invention.

FIELD OF THE INVENTION

The present invention relates to the mammalian gene 22444, a novel geneassociated with the susceptibility of an individual for developing orhaving a neuropsychiatric disorder such as schizophrenia,schizoaffective disorder or serious mood disorders including bipolardisorder and recurrent unipolar disorder. The present inventionencompasses 22444 nucleic acids, recombinant DNA molecules, cloned genesand variants thereof, 22444 gene products, cloning vectors containingmammalian 22444 gene molecules and host cells genetically engineered toexpress these molecules. The present invention also relates to methodsof identifying compounds which modulate expression of 22444 and to theuse of these compositions as therapeutic agents in the treatment ofthese neuropsychiatric disorders. In addition, the present inventionrelates to methods for diagnostic evaluation, genetic testing andprognosis of neuropsychiatric disorders associated with the 22444 gene.Identification of individuals with mutations in the sequences of the22444 gene of the present invention is useful as a diagnostic aide forvarious neuropsychiatric disorders, and in particular schizophrenia,schizoaffective disorders, bipolar disorder and recurrent unipolardisorder.

BACKGROUND OF THE INVENTION

Historically, schizophrenia (SZ) and bipolar (BP) disorder have beenconsidered as non-overlapping nosological entities, with distinctiveclinical characteristics, unique treatment regimens and separate (albeitunknown) etiologies.

The schizophrenic disorders are a group of syndromes manifested bymassive disruption of thinking, mood, and overall behavior as well aspoor filtering of stimuli. Diagnosis of schizophrenic disorder iscurrently based upon the presence of a number of behavioralcharacteristics of at least six months duration including: slowlyprogressive social withdrawal usually often accompanied by adeterioration in personal care; loss of ego boundaries with theinability to perceive oneself as a separate entity; loose thoughtassociations, often with slowed thinking or overinclusive and rapidshifting from topic to topic; autistic absorption in inner thoughts andfrequent sexual or religious preoccupations; auditory hallucinations,often of a derogatory nature; and delusions, frequently of grandiose orpersecutory nature. Frequent additional signs include: flat effect andrapidly alternating mood shift irrespective of circumstances;hypersensitivity to environmental stimuli, with a feeling of enhancedsensory awareness; variability or changeable behavior incongruent withthe external environment; concrete thinking with the inability toabstract; inappropriate symbolism; impaired concentration worsened byhallucinations and delusions; and depersonalization, wherein one behaveslike a detached observer of one's own actions. Diagnosis of aschizophrenic disorder based upon these behaviors can thus be quitearbitrary and is influenced by sociocultural factors and schools ofpsychiatric thought. At present, there is no laboratory method forconfirmation of a diagnosis of schizophrenia.

Bipolar disorder, also known as manic-depressive illness, involvescycles of mania and depression. Signs and symptoms of mania include:extreme irritability and distractibility; excessive euphoric feelings; asustained period of behavior that is different from the usual behavior;increased energy activity, restlessness, racing thoughts and rapidtalking; decreased need for sleep; unrealistic beliefs in one'sabilities and powers; uncharacteristically poor judgment; increasedsexual drive; abuse of drugs, particularly cocaine, alcohol and sleepingmedications; obnoxious, provocative or intrusive behavior and denialthat anything is wrong. Signs and symptoms of depression include:persistent sad, anxious or empty mood; feeling of hopelessness orpessimism; feeling of guilt, worthlessness or helplessness; loss ofinterest or pleasure in ordinary activities; decreased energy, a feelingof fatigue or of being “slowed down”; difficulty concentrating,remembering and making decisions; restlessness and irritability; sleepdisturbances; loss of appetite and weight, or weight gain; chronic painor other persistent bodily symptoms that are not caused by physicaldisease; and thoughts of death or suicide. Most people withmanic-depressive illness can be helped with treatment. However,manic-depressive illness, which is currently diagnosed by symptomsalone, is often not recognized by the patient, relatives, friends andeven physicians. If left untreated, bipolar disorder tends to worsen,and the person experiences episodes of full-fledged mania and clinicaldepression.

Accordingly, there is a need for better, more definitive diagnosticmarkers and methods for diagnosing neuropsychiatric disorders includingschizophrenia and bipolar disorder and other related disorders.

U.S. Pat. No. 5,866,412 discloses a mammalian gene, fsh15w6, which isassociated with bipolar affective disorder in humans. U.S. Pat. No.5,914,394 discloses a mammalian gene fsh16, which is associated withbipolar affective disorder. U.S. Pat. No. 5,939,316 discloses amammalian gene, fsh22, which is associated with bipolar affectivedisorder. U.S. Pat. No. 5,955,355 discloses a mammalian gene, fsh05,which is associated with bipolar affective disorder.

In the present invention, a new mammalian gene associated withneuropsychiatric disorders, referred to herein as 22444, has beenidentified.

SUMMARY OF THE INVENTION

The object of the present invention is to identify genes associated withneuropsychiatric disorders, to provide methods of treating anddiagnosing neuropsychiatric disorders, and to provide methods foridentifying compounds for use in these therapeutic and diagnosticmethods.

In particular, an object of the present invention is to provide amammalian gene, 22444, which is associated with neuropsychiatricdisorders including schizophrenia, schizoaffective disorder and seriousmood disorders including bipolar disorder and recurrent unipolardisorder, and nucleic acid sequences, recombinant DNA molecules, clonedgenes and variants thereof, of 22444.

Another object of the present invention is to provide mammalian 22444gene products and antibodies immunospecific for these 22444 geneproducts, or fragments or variants thereof.

22444 nucleic acid sequences and amino acid sequences are disclosedherein. Accordingly, another object of the present invention is toprovide vectors, preferably expression vectors, comprising mammalian22444, and host cells genetically engineered to express mammalian 22444gene products.

Another object of the present invention is to provide methods of use ofthe 22444 gene and 22444 gene products for the diagnostic evaluation,genetic testing and prognosis of a neuropsychiatric disorder. Forexample, in one embodiment, a method is provided for predicting thesusceptibility or predisposition of an individual to having ordeveloping neuropsychiatric disorders including schizophrenia,schizoaffective disorder and serious mood disorders such as bipolardisorder and recurrent unipolar disorder by detecting for the presenceor absence of the 22444 gene of gene product or mutations. In thismethod, the absence of the 22444 gene or gene product or the presence ofa mutation thereof is predictive of susceptibility or predisposition ofan individual to having or developing one of these neuropsychiatricdisorders. In another embodiment, a method is provided for diagnosingneuropsychiatric disorders such as schizophrenia, schizoaffectivedisorder, and serious mood disorders including bipolar disorder andrecurrent unipolar disorder in an individual by analyzing for thepresence or absence of the 22444 gene or gene product or a variantthereof in a biological sample obtained from the individual. In thismethod, the absence of the 22444 gene or gene product or the presence ofa variant thereof is indicative of the individual having aneuropsychiatric disorder.

Another object of the present invention is to provide new treatments andmethods of identifying new treatments for neuropsychiatric disorders. Inone embodiment, these treatments involve modulation of the expression ofthe mammalian 22444 gene and/or the activity or synthesis of a mammalian22444 gene product. In another embodiment, treatments involve supplyingthe mammal with a nucleic acid molecule encoding normal 22444. Methodsfor identifying new treatments involving modulation of the expression ofthe 22444 gene and/or the synthesis or activity of 22444 gene productscomprise contacting a compound to a cell that expresses a 22444 gene,measuring the level of 22444 gene expression, gene product expression orgene product activity produced by the cell and comparing this level tothe level of 22444 gene expression, gene product expression or geneproduct activity in the cell in the absence of the compound. Compoundswhich alter the level of 22444 gene expression, gene product expressionor gene product activity are thus identified as modulators of 22444 geneexpression or gene product synthesis or activity.

DETAILED DESCRIPTION OF THE INVENTION

A review of genetic epidemiology and recent molecular linkage studieshas revealed a high degree of concordance for schizophrenia genetics andbipolar disorder genetics. Specifically, genetic epidemiologic studieshave revealed that relatives of bipolar (BP) probands are at increasedrisk for recurrent unipolar (RUP), BP and schizoaffective (SA)disorders, while relatives of schizophrenia (SZ) probands are atincreased risk for SZ, SA and RUP disorders. The overlap in familialrisk is believed to reflect shared genetic susceptibility. Recentgenetic linkage studies have defined confirmed susceptibility loci forBP disorder for multiple regions of the human genome, including 4p16,12q24, 18p11.2, 18q22, 21q21, 22q11-13 and Xq26. Studies of SZ kindredshave yielded robust evidence for susceptibility at 18p11.2 and 22q11-13,both of which are implicated in susceptibility to BP disorder.Similarly, confirmed SZ vulnerability loci have been mapped to for 6p24,8p and 13q32. Strong statistical evidence for a 13q32 BP susceptibilitylocus has been reported. Thus, both family and molecular studies ofthese disorders suggest shared genetic susceptibility. Accordingly,these two group of disorders may not be so distinct as current nosologysuggests.

Significant evidence for a BP susceptibility locus on chromosome 18using affected sibling pair (ASP) and affected pedigree member (APM)methods (p=10⁻⁴-10⁻⁵), obtained in 22 Caucasian kindreds of Europeanancestry has been reported (Berrettini et al. Proc. Natl Acad. Sci. USA1994 91:5918-5921; and Berrettini et al. Arch. Gen. Psychiatry 1997 54:32-39). Evidence for linkage appears to be more prominent in thosefamilies with paternally transmitted illness (Stine et al., Am. J. Hum.Genet. 1995 57:1384-1394; Gershon et al. Neuropsychiatric Genetics 199667:1-8; Nothen et al. Molecular Psychiatry 1999 4:76; Knowles et al. Am.J. Hum. Genet. 1998 62:916-24).

Genetic Analysis Workshop 10 (Goldin et al. Genetic Epidemiology 199714:563-8) allowed statistical geneticists to analyze data fromBerrettini et al. Arch. Gen. Psychiatry 1997 54: 32-39; Nothen et al.Am. J. Hum. Genet. 1997 61(S): A288; Stine et al. Am. J. Hum. Genet.1995 57:1384-1394; Knowles et al. Am. J. Hum. Genet. 1998 62:916-24; andKalsi et al. Hum. Heredity 1997 47:268-78. Results of several differentanalyses were consistent with the existence of a BP susceptibility gene.For example, the entire data set of 382 affected sibling pairs (assumingBP, SA and RUP as affected) was analyzed using a non-parametric method(Lin, J. P. and Bale, S. J. Genetic Epidemiology 1997 14:665-8). AtD18S37, for 382 affected sibling pairs excess allele sharing (58%) wasevident, with p=2.8×10⁻⁸. Thus, there is a confirmed BP susceptibilitylocus on chromosome 18p11.2

Approximately 20 chromosome 18 markers were employed in a linkage studyof 59 multiplex German and Israeli schizophrenic (SZ) pedigrees, inwhich there were 24 affective disorder cases (2 were BP)(Schwab et al.Am. J. Hum. Genet. 1998 63: 1139). When these data were analyzed intwo-point parametric methods, the maximum lod score was 3.1 at D18S53. Amultipoint non-parametric analysis revealed LOD=2.9, p=0.0002, atD18S53. The SZ kindreds studied for 18p11 linkage are not nosologicallyor genetically distinct from other multiplex SZ kindreds. For example,these kindreds show linkage to chromosome 6p (Schwab et al. NatureGenetics 1995 11:325-7), as reported in other series of multiplex SZkindreds (Straub et al. Nature Genetics 1995 11:287-93; Moises et al.Nature Genetics 1995 11:321-4). Nosological mis-classification does notexplain the chromosome 18p11.2 linkage to SZ detected by Schwab et al.Am. J. Hum. Genet. 1998 63: 1139.

Thus, the 18p11.2 region has a confirmed BP susceptibility locus, andthere is a statistically impressive report of linkage at this locus inSZ.

A susceptibility gene for neuropsychiatric disorders including SZ and BPhas now been identified at the 18p11.2 susceptibility locus. Otherneuropsychiatric disorders which are believed to be related to this geneinclude schizoaffective disorder and other serious mood disorders suchas recurrent unipolar disorder. The isolated nucleotide sequence of thissusceptibility gene is depicted in SEQ ID NO:1. This mammalian gene isreferred to herein as 22444. The deduced amino acid sequence of a geneproduct encoded by this nucleic acid sequence is depicted in SEQ IDNO:2. The absence of this mammalian gene or an encoded gene product orthe presence of variant gene or gene product thereof are believed to beindicative of the susceptibility of an individual to developing and/orhaving a neuropsychiatric disorder such as schizophrenia,schizoaffective disorder, or serious mood disorders including bipolardisorder and recurrent unipolar disorder. Accordingly, the presentinvention relates to the 22444 gene and 2244 gene products and their useas diagnostic markers for ascertaining susceptibility or predispositionof an individual to developing and/or having a neuropsychiatric disordersuch as schizophrenia, schizoaffective disorder, or serious mooddisorders including bipolar disorder and recurrent unipolar disorder.The 22444 genes and gene products and variants thereof are also usefulin identifying new treatments and treating neuropsychiatric disorders.

As used herein by “22444 gene” it is meant a nucleic acid moleculecontaining the DNA sequence of SEQ ID NO:1; any DNA sequence thatencodes a polypeptide containing the amino acid sequence comprising SEQID NO:2; and any DNA sequence that hybridizes to the complement of theDNA sequences that encode an amino acid sequence comprising SEQ ID NO:2under moderately stringent conditions. By “moderately stringentconditions” it is meant conditions such as those described by Ausubel etal. (1989 Current Protocols in Molecular Biology, Vol. I, GreenPublishing Associates, Inc. and John Wiley & Sons, Inc. N.Y.). As usedherein, “22444 gene” also refers to degenerate variants encoding 22444gene products. 22444 genes can include both genomic DNA or cDNA and mRNAtranscribed by the genomic DNA.

The present invention also relates 22444 gene products. By “22444 geneproducts” it is meant to include amino acid sequences encoded by thenormal and variant 22444 genes. This term is also meant to includefunctionally equivalent 22444 gene products. By “functionallyequivalent” it is meant a gene product with at least one biologicalactivity which is the same as the normal 22444 gene product.Accordingly, contacting cells with a functionally equivalent 22444 geneproduct can inhibit or delay the onset of one or more symptoms of aneuropsychiatric disorder.

Also provided in the present invention are nucleic acid sequences,either DNA, RNA or a combination thereof which hybridize to the 22444gene. Such hybridization may occur under moderately stringentconditions, or more preferably highly stringent conditions. Suchconditions are well known in the art and discussed in detail inreferences such as Ausubel et al. (1989 Current Protocols in MolecularBiology, Vol. I, Green Publishing Associates, Inc. and John Wiley &Sons, Inc. N.Y.). These nucleic acid sequences can be used as probes inthe detection of normal and variant 22444 genes. These nucleic acidsequences can also be used as antisense agents altering expression ofnormal or variant 22444 genes. The present invention also relates tovectors comprising 22444 genes and nucleic acid sequences whichhybridize to the 22444 gene. In a preferred embodiment, the vectors areexpression vectors with a regulatory element which directs expression ofthe 22444 gene or the nucleic acid sequence. The present invention alsorelates to host cells genetically engineered to express 22444 geneproducts.

22444 genes, 22444 gene products and variants thereof as well as nucleicacid sequences hybridizing to the 22444 gene are useful in diagnosingneuropsychiatric disorders, identifying new treatments forneuropsychiatric disorders and in treating neuropsychiatric disorders.

In one embodiment, individuals with a predisposition to developing orhaving a neuropsychiatric disorder such as schizophrenia,schizoaffective disorder, or serious mood disorders including bipolardisorder and recurrent unipolar disorder are identified by detectingvariations in the 22444 gene of SEQ ID NO:1 or an absence of the 22444gene of SEQ ID NO:1. Methods for identifying individuals with a knownnucleotide sequence or variants thereof are well known in the art.Examples of such methods include, but are not limited, polymerase chainreaction (PCR), ligase chain reaction (LCR) and nucleic acid sequencebased amplification (NASABA). Reverse-transcriptase PCR (RT-PCR) is alsoa powerful technique which can be used to detect the presence of aspecific mRNA populations in a complex mixture of thousands of othermRNA species. In RT-PCR, an mRNA species is first reverse transcribed tocomplementary DNA (cDNA) with use of the enzyme reverse transcriptase;the cDNA is then amplified as in a standard PCR reaction. RT-PCR canthus reveal by amplification the presence of a single species of mRNA.Hybridization to clones or oligonucleotides arrayed on a solid support(i.e. gridding) can also be used to detect the presence of a selectednucleotide sequence.

In this method a DNA-containing biological sample is obtained from anindividual. DNA or mRNA in the biological sample is then analyzed forthe presence or absence of the 22444 gene of SEQ ID NO:1 or a variantthereof. The absence of the 22444 gene of SEQ ID NO:1 and/or thepresence of a variant gene is indicative of the individual beingsusceptible to developing or having a neuropsychiatric disorder such asschizophrenia, schizoaffective disorder, or serious mood disordersincluding bipolar disorder and recurrent unipolar disorder.

Alternatively, biological samples obtained from an individual can alsobe analyzed for the presence of a variant 22444 gene product, such asthose depicted in the presence or absence of the 22444 gene product ofSEQ ID NO:2 to ascertain an individual's susceptibility to theneuropsychiatric disorders. Methods for detecting the presence orabsence of a known polypeptide sequence are well known in the art. The22444 gene product or variants and fragments thereof can be used toraise antibodies against the 22444 gene product or variant thereof. Suchantibodies can then be used in various assays to detect the presence orabsence of the 22444 gene product or variant thereof in a sample.Examples of these assays include, but are not limited to,radioimmunoassays, immunohistochemistry assays, competitive-bindingassays, Western Blot analyses, ELISA assays, proteomic approaches,two-dimensional gel electrophoresis (2D electrophoresis) and non-gelbased approaches such as mass spectrometry or protein interactionprofiling. In these methods, the presence of a variant 22444 geneproduct or the absence of the 22444 gene product of SEQ ID NO:2 isindicative of an individual being susceptible to developing or having aneuropsychiatric disorder such as schizophrenia, schizoaffectivedisorder, or serious mood disorders including bipolar disorder andrecurrent unipolar disorder.

The 22444 gene and 22444 gene products of SEQ ID NO:1 and SEQ ID NO:2also provide useful tools for development of new treatments for theseneuropsychiatric disorders. For example, as demonstrated hereinmutations in the nucleotide sequence of SEQ ID NO:1 leads to variantswith disrupted protein function in individuals with schizophrenia,schizoaffective disorder and serious mood disorders including bipolarand recurrent unipolar disorders. Accordingly, the 22444 gene product,agents which mimic the 22444 gene product or inhibit disruption in thefunction of the 22444 gene product may be useful in treating theseneuropsychiatric disorders. Alternatively, agents which alter expressionand/or levels of the normal protein may also be useful in the treatmentof these disorders. Such agents can be identified in routine screeningassays which examine levels of the 22444 gene or 22444 gene product asdepicted in SEQ ID NO:1 and SEQ ID NO:2. Agents identified as alteringlevels and/or expression of the gene or gene product of SEQ ID NO:1 andSEQ ID NO:2 are expected to be useful in the treatment of theseneuropsychiatric disorders.

The 22444 gene and 22444 gene products of SEQ ID NO:1 and SEQ ID NO:2are also useful in identifying other proteins and/or genes encoding suchproteins which interact with 22444 gene products. Various methods foridentifying such proteins and/or genes for encoding these proteins areknown in the art. Well known techniques include, but are not limited to,yeast two hybrid systems and receptor binding assays.

The following nonlimiting example is provided to further illustrate thepresent invention.

EXAMPLE

Genomic sequences from human chromosome 18, encoding the Golf(CA)repeat, as described by Berrettini et al. Psychiatric Genetics 19988:235-38, was used to generate genomic DNA sequence in the 5′ directionwithin Golf intron 5. This sequence was analyzed for possible exons.Primers were designed from a possible exon in the new genomic sequence.These primers were then used to screen human brain cDNA libraries.Clones from these libraries were sequenced to reveal the nucleotidesequence depicted as SEQ ID NO:1. Variation in this sequence, whichtruncates the encoded polypeptide prematurely, has been found. It isbelieved that this premature truncation of the protein predisposesindividuals to schizophrenia and serious mood disorders includingbipolar and recurrent unipolar disorder.

Common sequence variants were also screened for with the entire 2.9 kbcDNA in DNA samples from 50 unrelated BP individuals and 50 unrelatedpersons with SZ. Direct sequencing of a 450 bp fragment, including theentire 22444 coding region, did not reveal a common polymorphism (minorallele frequency >5%). The coding region, ˜25% of the 5′UTR and ˜15% ofthe 3′UTR has been screened in a search for variants. One 5′UTR singlenucleotide polymorphism (SP) was found which had a minor allelefrequency of ˜5%. A summary of the SNPs is given in the table below.Restric- tion allele freq in freq in bp{circumflex over ( )} sequenceenzyme cut EA* AA** G2808T CAGC(G/T)CAG HhaI G 0.62 0.78+ G3052ACCGC(G/A)GAA BstuI G 0.63 0.89# G3072A GAG(G/A)ACAC MnlI G ND{circumflexover ( )}{circumflex over ( )} ND G3117A CACT(G/A)GGT MaeI A ND ND A219GCTGCA(A/G)CA PstI G 0/034 0.12{circumflex over ( )}base pair from the cDNA of SEQ ID NO:1;{circumflex over ( )}{circumflex over ( )}ND, not determined.*frequency of the cut allele in Americans of European ancestry (EA);+Chi-square = 15.0, p = 0.0002, EA vs. AA frequency;**frequency of the cut allele in Americans of African ancestry (AA);#Chi-square = 32.7, p<0.00001, EA vs AA freq.

The G2808T and G3052A SNPs were genotyped in 171 unrelated individualsof European ancestry (EA). There was no deviation for Hardy-Weinbergequilibrium. Analysis of 48 African-Americans (AA) revealed significantdifferences in allele frequencies, compared to the EA group for G2808Tand for G3052A. Analysis with the EH program revealed LD between thesetwo SNPs (which are separated by 244 bp), with D=0.1 (Chi-square=14.7,p=0.005). Of the 171 unrelated EA individuals genotyped, 102 were SZ,while 69 were screened controls. There was LD between these SNPs and SZ.EH Program Output: Locus/Allele 1 2 Disease | 0.9000 0.1000 1 | 0.61990.3801 2 | 0.6345 0.3655

At these 3 loci, there are 8 possible haplotypes, listed below withtheir estimated frequencies. HAPLOTYPE FREQUENCY ASSUMING MarkersMarkers Allele Associated and at Allele at Allele at But Not DiseaseDisease Marker 1 Marker 2 Independent Disease Associated + 1 1 0.3539930.444062 0.321927 + 1 2 0.203883 0.113833 0.107816 + 2 1 0.2170910.126991 0.149206 + 2 2 0.125033 0.215114 0.321051 D 1 1 0.0393330.049340 0.078494 D 1 2 0.022654 0.012648 0.013306 D 2 1 0.0241210.014110 0.008200 D 2 2 0.013893 0.023901 0.000000

#param Ln (L) Chi-square H0: No Association 2 −297.09 0.00 H1: MarkersAssociated, 3 −289.27 15.63 independent of disease H2: Markers andDisease Associated 6 −283.37 27.43This analysis assumes a 10% disease allele frequency, but the resultsare very similar if the disease allele frequency is increased to 60%. Ifthe difference between the Chi-square values for H2 and H1 is theevidence for association with disease, then Chi-square=11.8, p=0.008.

1. An isolated mammalian 22444 gene.
 2. The isolated mammalian 22444 gene of claim 1 comprising a nucleic acid sequence of SEQ ID NO:1.
 3. A vector comprising the isolated mammalian 22444 gene of claim
 1. 4. A host cell expressing the vector of claim
 3. 5. An isolated mammalian 22444 gene product.
 6. The isolated mammalian 22444 gene product of claim 5 comprising an amino acid sequence of SEQ ID NO:2.
 7. An antibody raised against the mammalian 22444 gene product of claim
 5. 8. A diagnostic marker for predicting susceptibility of an individual to having or developing a neuropsychiatric disorder comprising the isolated mammalian 22444 gene of claim 1 or a mammalian 22444 gene product.
 9. A method for predicting the susceptibility of an individual for having or developing a neuropsychiatric disorder comprising obtaining a biological sample from the individual and screening the biological sample for the presence or absence of the mammalian 22444 gene of claim 1 or a variant thereof wherein the absence of the nucleotide sequence or the presence of the variant is indicative of a susceptibility of the individual to have or develop a neuropsychiatric disorder.
 10. A method for predicting the susceptibility of an individual for having or developing a neuropsychiatric disorder comprising obtaining a biological sample from the individual and screening the biological sample for the presence or absence of the mammalian 22444 gene product of claim 5 or a variant thereof wherein the absence of the mammalian 22444 gene product or the presence of the variant is indicative of a susceptibility of the individual to have or develop a neuropsychiatric disorder.
 11. A method of diagnosing a neuropsychiatric disorder in an individual comprising obtaining a biological sample from the individual and analyzing the biological sample for the presence or absence of the mammalian 22444 gene of claim 1 or a variant thereof wherein the absence of the mammalian 22444 gene or the presence of the variant is indicative of a neuropsychiatric disorder.
 12. A method of diagnosing a neuropsychiatric disorder in an individual comprising obtaining a biological sample from the individual and analyzing the biological sample for the presence or absence of the mammalian 22444 gene product of claim 5 or a variant thereof wherein the absence of the 22444 gene product or the presence of the variant is indicative of a neuropsychiatric disorder.
 13. A method of identifying potential agents for use in the treatment of neuropsychiatric disorders comprising screening agents for an ability to alter expression or levels of the mammalian 22444 gene of claim 1 or a 22444 gene product encoded thereby or to mimic the 22444 gene product encoded thereby.
 14. A composition for the treatment of neuropsychiatric disorders comprising an agent which alters expression or levels of the mammalian 22444 gene of claim 1 or a 22444 gene product encoded thereby or mimics the 22444 gene product encoded thereby.
 15. A composition for the treatment of neuropsychiatric disorders comprising a 22444 gene product of claim
 5. 16. A method for identifying proteins which interact with 22444 gene products comprising contacting the 22444 gene product of claim 5 with a protein suspected of interacting with the 22444 gene product and determining whether the protein interacts with the 22444 gene product. 